Association between Dietary Acid Load and Chronic Kidney Disease in the Chinese Population: A Comprehensive Analysis of the China Health and Nutrition Survey (2009)

Background: Dietary acid load (DAL) is closely related to several chronic diseases. However, the link between DAL and chronic kidney disease (CKD) remains scarce and without data from the Chinese populations whose diet is quite different from people in Western countries. Methods: This study evaluated DAL by potential renal acid load (PRAL) and net endogenous acid production (NEAP). We clarified the relationship between DAL and CKD by logistic regression analysis based on data from the China Health and Nutrition Survey (CHNS). Results: The final analysis included 7699 individuals, of whom 811 (11.44%) were CKD patients. Although there was no notable link between PRAL and CKD, higher NEAP levels were independently correlated with CKD. As NEAP values rise, so does CKD prevalence. This trend remains highly significant even after adjustments. In subgroup analyses, the relationship between NEAP and CKD was more consistent in the elderly and subjects with a waistline of less than 82 cm and those without diabetes and heart disease. RCS analysis further confirmed the clear linear relationship between the OR of CKD and NEAP score. Conclusions: This study highlighted that higher NEAP was positively correlated with the risk of CKD.


Introduction
In the preceding twenty years, the incidence and mortality rates of CKD have gradually increased worldwide.According to The Lancet, in 2019, there were 697.5 million patients with CKD globally, constituting 9.1% of the world's population from 1990 to 2017 [1].This prevalence surpasses non-communicable chronic diseases such as metabolic disorders, cardio-cerebrovascular disease, bronchopneumonia, and gastroenteritis [2].Even more remarkably, 90% of adults affected by CKD are unaware of their condition, and half of those with diminished kidney function who are not undergoing dialysis are oblivious to the presence of CKD.Therefore, the early blocking of the progress of CKD is beneficial to reducing the morbidity and mortality of ESRD.
Recently, besides pharmacological therapies, medical nutrition and dietary intervention were recognized as effective strategies for preventing and treating CKD.Many studies have confirmed that diet interventions are convenient, inexpensive, and practical methods in CKD therapies [3,4].The appropriate intake of proteins, phosphorus, sodium, and potassium could effectively prevent or improve the symptoms of insufficient renal function, diminishing proteinuria, maintaining good nutritional status, and avoiding malnutrition and metabolic disorders [5][6][7].These metabolic disturbances comprise a cluster of dysfunctions, including protein-energy wasting, malnutrition, and progressive decreases in muscle function, all of which might accelerate CKD progression and heighten the incidence of complications, including frailty, cardiovascular disease, disturbed blood control, infectious complication, and the mortality of CKD and ESRD patients [8].Intuitively, the disorders of acid-base balance are the most common complication of CKD and aggravate gastrointestinal symptoms [9].There is compelling evidence that DAL is the primary determinant of the acid-base balance and systemic pH clinical research has shown a positive correlation between DAL and metabolic syndromes, chronic inflammation, hypertension, and hyperuricemia [10][11][12][13], which all contribute to CKD progression.
In animal experiments, DAL is associated with increased protein intake, leading to a reduction in renal medullary and muscle pH accompanied by an elevation in ammonia concentration.Clinical studies indicated that diets rich in fruits and vegetables buffered DAL, attenuating kidney injury and slowing GFR decline [14,15].Tanushree demonstrated that the prevalence of kidney failure was threefold higher for people with higher DAL than those with lower DAL [16].Crews suggested that the effect of DAL on CKD patients may vary by ethnicity and race-related perceptions, which suggests that these clinical outcomes in Western countries, as described in previous studies, may not be beneficial to the Asia population [17].Unfortunately, no investigation has focused on the relationship between DAL and CKD in the Chinese population.
To fill this gap, we conducted this study based on cross-sectional data from the CHNS, which collected extensive community-level data from 1989 to 2015 in China [18].Therefore, this study aims to determine the association between DAL and CKD in a large Chinese population.The results will provide new perspectives on the diagnosis and prognosis of CKD patients while also developing innovative strategies and public health policies to enhance the quality of life and life expectancy of the elderly population.

Data Collection and Participants
This study utilized openly accessible data from the CHNS.This study utilized a multistage random clustering method to gather comprehensive data on the socioeconomic status, healthcare utilization, dietary habits, and nutritional status of a consistent cohort over time.Finally, we selected approximately 7200 households, with a total population exceeding 30,000 individuals.
We gathered essential particulars, health-related data, socioeconomic status, diet and exercise information derived from the 2009 database, and exclusively biological data.A total of 7749 participants were recruited from 18,805 individuals in this study, excluding individuals with incomplete information, missing variables, no EGFR data, and those under 18 years old (Figure 1).and metabolic disorders [5][6][7].These metabolic disturbances comprise a cluster of dysfunctions, including protein-energy wasting, malnutrition, and progressive decreases in muscle function, all of which might accelerate CKD progression and heighten the incidence of complications, including frailty, cardiovascular disease, disturbed blood control, infectious complication, and the mortality of CKD and ESRD patients [8].Intuitively, the disorders of acidbase balance are the most common complication of CKD and aggravate gastrointestinal symptoms [9].There is compelling evidence that DAL is the primary determinant of the acid-base balance and systemic pH clinical research has shown a positive correlation between DAL and metabolic syndromes, chronic inflammation, hypertension, and hyperuricemia [10][11][12][13], which all contribute to CKD progression.
In animal experiments, DAL is associated with increased protein intake, leading to a reduction in renal medullary and muscle pH accompanied by an elevation in ammonia concentration.Clinical studies indicated that diets rich in fruits and vegetables buffered DAL, attenuating kidney injury and slowing GFR decline [14,15].Tanushree demonstrated that the prevalence of kidney failure was threefold higher for people with higher DAL than those with lower DAL [16].Crews suggested that the effect of DAL on CKD patients may vary by ethnicity and race-related perceptions, which suggests that these clinical outcomes in Western countries, as described in previous studies, may not be beneficial to the Asia population [17].Unfortunately, no investigation has focused on the relationship between DAL and CKD in the Chinese population.
To fill this gap, we conducted this study based on cross-sectional data from the CHNS, which collected extensive community-level data from 1989 to 2015 in China [18].Therefore, this study aims to determine the association between DAL and CKD in a large Chinese population.The results will provide new perspectives on the diagnosis and prognosis of CKD patients while also developing innovative strategies and public health policies to enhance the quality of life and life expectancy of the elderly population.

Data Collection and Participants
This study utilized openly accessible data from the CHNS.This study utilized a multistage random clustering method to gather comprehensive data on the socioeconomic status, healthcare utilization, dietary habits, and nutritional status of a consistent cohort over time.Finally, we selected approximately 7200 households, with a total population exceeding 30,000 individuals.
We gathered essential particulars, health-related data, socioeconomic status, diet and exercise information derived from the 2009 database, and exclusively biological data.A total of 7749 participants were recruited from 18,805 individuals in this study, excluding individuals with incomplete information, missing variables, no EGFR data, and those under 18 years old (Figure 1).All the participants provided informed consent.The study was approved by the Carolina Population Center at the University of North Carolina and the National Institute of Nutrition and Health Research at the Chinese Center.

Predictors-Dietary Acid Load Estimations
The dietary information was gathered by instructing the participants to record their daily food intake.Strictly speaking, the participants should document the types and quantities of food they consume within 24 h, covering two workdays and one weekday.The nutrient and energy intake were measured based on the Chinese Food Composition Tables as follows [14,19]:

Statistical Analysis
Continuous variables were summarized as mean (SD) or median (IQR), and categorical variables as frequencies.Group comparisons utilized Student's t-test, Fisher's exact test, or chi-square test, as appropriate.
Both univariate and multilevel logistic regression analyses were used to identify the association between CKD and DAL.We categorized the individuals into four groups according to the quartile distribution (Q1, Q2, Q3, and Q4); the odds ratios (ORs) were calculated based on the quartiles of the DAL score.Then, we conducted five models; model 1: unadjusted for covariates; model 2: adjusted for demographic variables; model 3: adjusted for hypertension, diabetes, heart disease, and fraction.Model 4: adjusted for hypertension, diabetes, heart disease, and fraction based on model 2; model 5: adjusted for energy, fat, cholesterol, CHO, and water.We also performed a subgroup analysis according to gender, age, and the absence of comorbidities (diabetes, hypertension, and heart disease).In the end, a restricted cubic spline (RCS) analysis was employed to demonstrate the relationship between CKD and DAL.Significance was set at p < 0.05.

Baseline Characteristics
In this study, a total of 7749 individuals were included (Figure 1), and the general characteristics of the participants are presented in Table 1.In all, 895 patients (11.55%) were diagnosed with CKD with a mean age of 50.2 ± 15.0 years, and 22.7% had a high school or higher education.About one-third of them had a history of tobacco smoking (31.06%) or alcohol intake (32.68%).The underlying diseases included hypertension (13.06%), diabetes (2.79%), and cardiovascular disease (0.94%).

Association between DAL and CKD
There was no significant association between CKD and PRAL in the five multivariate logistic regression models adjusted by different covariates (Table 3).The relationship between NEAP and CKD was shown in five logistic regression models, and an elevated level of NEAP was an independent association factor for CKD risk in the adjusted models 2, 3, 4, and 5 (Table 4).

Subgroup Analysis for the Association between DAL and CKD
In the subgroup analyses, there was no significant association between PRAL and the risk of CKD with the factors (gender, age, waist, BMI, and comorbidities, including diabetes, hypertension, and heart disease) responsible for potential heterogeneity (Figures S1A and S2A).However, we observed that the positive correlation between NEAP and CKD appeared stronger in those aged ≥ 60 years with lower waist circumference and BMI < 24 kg/m 2 .Further, in the subgroup without heart disease (Q3: OR 1.30, 95% CI 1.01-1.69;Q4: OR 1.32, 95% CI 1.00-1.75)and diabetes 1.32 (95% CI, 1.01-1.72)and 1.34 (95% CI, 1.01-1.78)participants were more likely to suffer from CKD after adjusting for all the confounders, but not in subjects with or without cardiovascular disease (Figure S2B).

RCS Analysis of DAL and Risk of CKD
The RCS analysis showed non-linear associations between the OR values of CKD and PRAL (p > 0.05; Figure 2A) based on the multivariate logistic proportional hazards model.However, the NEAP score increased the risk of CKD (p < 0.05), which revealed a clear linear relationship between the OR values of CKD and NEAP with the cutoff of 77.99 mEq/day (Figure 2B).

Dietary Intakes and CKD Risk in an Energy-Adjusted Model
In the energy-adjusted model, we found that protein and fat increased the risk of CKD by 16% (OR: 1.16, 95% CI: 1.06-1.27)for each 10 g increased intake, and each 100 g fat and carbohydrate intake may increase the risk of CKD by 95% (OR: 1.95, 95% CI: 1.41-2.68)and

Dietary Intakes and CKD Risk in an Energy-Adjusted Model
In the energy-adjusted model, we found that protein and fat increased the risk of CKD by 16% (OR: 1.16, 95% CI: 1.06-1.27)for each 10 g increased intake, and each 100 g fat and carbohydrate intake may increase the risk of CKD by 95% (OR: 1.95, 95% CI: 1.41-2.68)and 21% (OR: 1.23, 95% CI: 1.08-1.4)respectively.In addition, calcium was also observed to increase the risk of CKD by 20% for each 100 g increased intake.However, for every 100 mg reduction in energy-adjusted phosphorus and magnesium intake, the risk of CKD may decrease by 17% and 18%, respectively (Figure 3).

Dietary Intakes and CKD Risk in an Energy-Adjusted Model
In the energy-adjusted model, we found that protein and fat increased the risk of CKD by 16% (OR: 1.16, 95% CI: 1.06-1.27)for each 10 g increased intake, and each 100 g fat and carbohydrate intake may increase the risk of CKD by 95% (OR: 1.95, 95% CI: 1.41-2.68)and 21% (OR: 1.23, 95% CI: 1.08-1.4)respectively.In addition, calcium was also observed to increase the risk of CKD by 20% for each 100 g increased intake.However, for every 100 mg reduction in energy-adjusted phosphorus and magnesium intake, the risk of CKD may decrease by 17% and 18%, respectively (Figure 3).

Discussion
As the first multicenter national cross-sectional study in China, we first identified a significant correlation between elevated levels of NEAP and an increased risk of CKD.In the subgroup analyses, the correlation between NEAP and CKD was more consistent in the elderly, waist < 82 cm, and those without diabetes, and heart diseases.The RCS analysis further indicated a clear linear relationship between the OR of the CKD and NEAP score.In addition, we confirmed that higher consumption of carbohydrates, fat, and protein was correlated with an increased risk of CKD.
Dietary intake is a crucial factor influencing the acid-base balance in individuals with chronic diseases.A substantial body of research has developed various methods to estimate DAL based on dietary intake measurements including endogenous acid production, gastrointestinal (GI) alkali absorption, NEAP, net acid excretion NAE, and PRAL [22][23][24][25].The most prevalent methodologies for assessing acid-base balance are NEAP and the diet-dependent component of net acid excretion, referred to as PRAL [25,26], both of which assess acid-base status based on food components such as calcium, phosphorus, magnesium, protein, and potassium.NEAP, calculated from the ratio of dietary protein to potassium content,

Discussion
As the first multicenter national cross-sectional study in China, we first identified a significant correlation between elevated levels of NEAP and an increased risk of CKD.In the subgroup analyses, the correlation between NEAP and CKD was more consistent in the elderly, waist < 82 cm, and those without diabetes, and heart diseases.The RCS analysis further indicated a clear linear relationship between the OR of the CKD and NEAP score.In addition, we confirmed that higher consumption of carbohydrates, fat, and protein was correlated with an increased risk of CKD.
Dietary intake is a crucial factor influencing the acid-base balance in individuals with chronic diseases.A substantial body of research has developed various methods to estimate DAL based on dietary intake measurements including endogenous acid production, gastrointestinal (GI) alkali absorption, NEAP, net acid excretion NAE, and PRAL [22][23][24][25].The most prevalent methodologies for assessing acid-base balance are NEAP and the diet-dependent component of net acid excretion, referred to as PRAL [25,26], both of which assess acid-base status based on food components such as calcium, phosphorus, magnesium, protein, and potassium.NEAP, calculated from the ratio of dietary protein to potassium content, indicates the equilibrium between acid and base precursors in the body.In this study, we first observed that NEAP was positively significantly correlated with the prevalence of CKD in the Chinese population.It filled the gap of Chinese data in this controversial field.This conclusion was inconsistent with previous studies from European and American countries and some Asian regions.Clinical research from Johns Hopkins University suggested that a higher NEAP was correlated with a higher CKD incidence independent of sociodemographic, clinical, and lifestyle factors in a population-based sample [27].The African American Study drew similar conclusions that higher estimated NEAP predicts a faster decline in directly measured I125 iothalamate GFR [28].Kabasawa and colleagues from Japan demonstrated that elevated NEAP levels were correlated with the presence of albuminuria, which serves as a marker for CKD [29].In Banerjee's crosssectional cohort study, higher NEAP value was strongly associated with progression to ESRD (HR 3.04 (1.58 to 5.86)) [16].However, Pike and colleagues found no associations between the NEAP score and CKD progression in any APOL1 genotype [30].Scialla and colleagues observed that a higher NEAP was correlated with the increased consumption of meat and poultry and decreased intake of fruits and vegetables, but it was not linked to the progression of CKD.However, elevated NEAP estimated from urine biomarkers (NEAP Urine ) was correlated with a higher risk of CKD in individuals without diabetes [31].
Then, we further conducted sensitivity analyses to see if our results were robust.In this study, we found that older adults and individuals with smaller waist circumferences tended to have higher acid load.Elderly individuals often experience a reduction in muscle mass, insufficient nutritional intake, decreased metabolic efficiency, weakened buffering system function, and chronic diseases [32][33][34].These factors contribute to a diminished ability to buffer acids, resulting in an increased acid load in the body [34,35].Additionally, people with smaller waist circumferences often have less muscle mass and fat reserves, which can lead to disturbances in acid-base balance, and are more susceptible to the effects of NEAP [36,37].These findings underscore the significance of body composition and muscle mass in evaluating dietary acid load and its health repercussions, particularly in vulnerable elderly groups.In addition, we also found that CKD patients without diabetes and heart disease may be more susceptible to the effects of NEAP.This result is consistent with a previous cross-sectional study in Korea, which suggested that the relationship between eNEAP and CKD appeared stronger in those without obesity, diabetes, and heart disease [38].These studies demonstrated that in CKD patients without diabetes or heart disease complications, effectively controlling DAL levels contributes significantly to reducing the risk of CKD.
We also confirmed that the people with higher intakes of carbohydrates, fat, and protein might be at an increased risk of CKD, consistent with the majority of the previously published studies [7].High protein, fat, and carbohydrate load might contribute to proteinuria and the disorder of electrolytic and acid-base balance, resulting in glomerular hyperfiltration and CKD progression [39][40][41][42][43]. Rebholz et al. demonstrated that a DASHstyle diet, a dietary pattern high in fruits, vegetables, low-fat, and carbohydrates, was a protective factor for CKD, and this pattern gives evidence for dietary approaches to the prevention and treatment of CKD [44].Similar findings from research on the Mediterranean diet (MD), which is characterized by the regular intake of plant-based foods, indicate that it can lower the levels of homocysteine, microalbuminuria, total cholesterol, and phosphorus while increasing vitamin B12 levels in the early stages of CKD [45].In conclusion, a traditional diet rich in plant-based proteins supports glomerular hemodynamics and offers protective benefits for renal function [46].
This study had several limitations.Firstly, as a cross-sectional study, it could not prove the cause-and-effect relations between DAL and CKD.Secondly, although PRAL and NEAP are widely used indicators of overall DAL, it is calculated by diet but not from the directly measured data.Thirdly, since dietary assessment came from the recall of food intake by the participants, recall bias could not be avoided, although we tried several ways to minimize it.Fourthly, due to the presence of some missing data (sampling framework, weight information, serum calcium, and serum phosphorus) in this population-based study, the conclusions may have certain limitations when applied to a broader population, particularly the Chinese population.

Conclusions
In conclusion, this study is the first to evaluate the relationship between DAL and CKD in the Chinese population.The graphical summary of the study is shown in Figure 4.It concluded that higher NEAP positively correlated with the prevalence of CKD, either with or without covariate adjustment.It may provide novel insights and strategies to improve the standard of living and life expectancy of the elderly population.

Conclusions
In conclusion, this study is the first to evaluate the relationship between DAL and CKD in the Chinese population.The graphical summary of the study is shown in Figure 4.It concluded that higher NEAP positively correlated with the prevalence of CKD, either with or without covariate adjustment.It may provide novel insights and strategies to improve the standard of living and life expectancy of the elderly population.Informed Consent Statement: Ethical approval was secured, and informed consent was acquired from all the participants engaged in the research.

Figure 1 .
Figure 1.Flow chart of research participant selection.Figure 1. Flow chart of research participant selection.

Figure 1 .
Figure 1.Flow chart of research participant selection.Figure 1. Flow chart of research participant selection.

Nutrients 2024 , 10 Figure 2 .
Figure 2. RCS of the correlation between the CKD risk (ORs) and PRAL (A) and NEAP (B).Pink solid line indicates cut-off value.

Figure 2 .
Figure 2. RCS of the correlation between the CKD risk (ORs) and PRAL (A) and NEAP (B).Pink solid line indicates cut-off value.

Figure 2 .
Figure 2. RCS of the correlation between the CKD risk (ORs) and PRAL (A) and NEAP (B).Pink solid line indicates cut-off value.

Figure 3 .
Figure 3. Forest plot of the relationship between dietary intakes and CKD risk (energy-adjusted model).

Figure 3 .
Figure 3. Forest plot of the relationship between dietary intakes and CKD risk (energy-adjusted model).

Figure 4 .
Figure 4. Graphical summary of this study.Supplementary Materials: The following supporting information can be downloaded at: www.mdpi.com/xxx/s1, Figure S1: Subgroup analysis examined the relationship between DAL and the risk of CKD; Figure S2: Subgroup analysis examined the relationship between DAL and the risk of CKD.Author Contributions: Research idea and study design: S.W., X.F., X.Z., P.X., H.Z. and L.C.; data analysis/interpretation: S.W., X.F., Z.Z. and L.C.; statistical analysis: S.W. and X.F.; supervision or mentorship: X.Z. and L.C.; writing-original draft preparation, S.W.; writing-review and editing, S.W., Z.Z. and L.C.; supervision, S.W., X.F., and L.C.; funding acquisition, L.C.All authors have read and agreed to the published version of the manuscript.Funding: This work was partially supported by grants from the National Science and Technology Major Project (2022ZD0116003 to C.L.), CAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-003 to C.L.), National High-Level Hospital Clinical Research Funding (2022-PUMCH-B-019, to C.L.), and the Capital Exemplary Research Wards Project (BCRW202001 to C.L.).Institutional Review Board Statement: Not applicable.

Table 1 .
Subject characteristics based on CKD status.

Table 3 .
ORs and 95% CI for CKD risk based on PRAL.

Table 4 .
ORs and 95% CI for CKD risk based on NEAP.
Notes: model 1: without covariate adjustment; model 2: adjusted for demographic data; model 3: adjusted for hypertension, diabetes, heart disease, and fraction; model 4: adjusted for hypertension, diabetes, heart disease, and fraction based on model 2; model 5: adjusted for energy, fat, cholesterol, CHO, and water.